Ligands of the Angiotensin II Type 2 Receptor : Exploring structure and function of the AT2R ligand C38

The renin-angiotensin-aldosterone-system (RAAS) control blood-pressure regulation, exerted by the main effector peptide angiotensin II (AngII) binding the angiotensin II type 1 receptor (AT1R). While hypertension is the most known disease caused by over-activity in RAAS, several proteins in the system exhibit protective functions. One of these protective proteins is the GPCR angiotensin II type 2 receptor (AT2R). After decades of research its biological role remain to be fully elucidated, exemplified by the two AT2R ligands currently in clinical trials; agonist C21 for treatment of idiopathic pulmonary fibrosis, and antagonist EMA401 for treatment of peripheral neuropathic pain. Making a minor structural change in C21 shifted the pharmacological profile, generating the regioisomer antagonist C38. The renewed interest in AT2R antagonists as potential drugs to treat neuropathic pain make continued studies of antagonist C38 highly interesting.  The aim of this thesis was to continue exploring the structure-activity relationship of antagonist C38 by investigating three chemical motifs to identify compounds with better drug-like properties. Developing a new chemical method, transesterification of sulfonyl carbamates, allowed quick modification of one of the motifs. Reducing the length of the sulfonyl carbamate chain significantly increased metabolic stability in liver microsomes without losing affinity for AT2R. Using a model substrate, the transesterification reaction was applied in a microwave heated continuous-flow system. Adding small substituents to the central phenyl ring generated a second library of ligands with retained affinity, but with no observed increase in metabolic stability. Docking studies with this library and a recently presented crystal structure of AT2R, resulted in a proposed binding mode of C38. Replacing the imidazole head group with bicyclic amides slightly improved affinity. While metabolic stability improved compared to previously published amide analogs, the bicyclic ligands were inferior to C38. Developing an assay based on RAW264.7 macrophages allowed a new evaluation of the functional activity exhibited by C38. In contrast to previous research, C21 and C38 both display agonistic functional activity in the macrophage assay. In summary, the work presented in this thesis expand the structure-activity relationship of C38 and its pharmacological profile. Two new ligands were identified that could serve as tools in murine models of neuropathic pain

Synthetic Approach to Dehaloperophoramidine via a Samarium Mediated Reductive Dialkylation

Marine ascidian metabolite perophoramidine has since its isolation in 2002 attracted the interest of several research groups. The complex polycyclic structure with vicinal quaternary carbon stereocenters and two amidine functionalities constitutes a formidable synthetic challenge. In this project a new synthetic approach to dehalogenated perophoramidine has been investigated. The vicinal quaternary carbon stereocenters were introduced via a samarium mediated reductive dialkylation, in which the stereochemistry was determined by the metal chelate that formed, as outlined below. Several of the steps suggested in the synthetic approach have been successfully evaluated. Future work is needed to assess the remaining steps of the suggested route to dehalogenated perophoramidine.                      

Synthetic Approach to Dehaloperophoramidine via a Samarium Mediated Reductive Dialkylation

Marine ascidian metabolite perophoramidine has since its isolation in 2002 attracted the interest of several research groups. The complex polycyclic structure with vicinal quaternary carbon stereocenters and two amidine functionalities constitutes a formidable synthetic challenge. In this project a new synthetic approach to dehalogenated perophoramidine has been investigated. The vicinal quaternary carbon stereocenters were introduced via a samarium mediated reductive dialkylation, in which the stereochemistry was determined by the metal chelate that formed, as outlined below. Several of the steps suggested in the synthetic approach have been successfully evaluated. Future work is needed to assess the remaining steps of the suggested route to dehalogenated perophoramidine.                      

Ligands of the Angiotensin II Type 2 Receptor : Exploring structure and function of the AT2R ligand C38

The renin-angiotensin-aldosterone-system (RAAS) control blood-pressure regulation, exerted by the main effector peptide angiotensin II (AngII) binding the angiotensin II type 1 receptor (AT1R). While hypertension is the most known disease caused by over-activity in RAAS, several proteins in the system exhibit protective functions. One of these protective proteins is the GPCR angiotensin II type 2 receptor (AT2R). After decades of research its biological role remain to be fully elucidated, exemplified by the two AT2R ligands currently in clinical trials; agonist C21 for treatment of idiopathic pulmonary fibrosis, and antagonist EMA401 for treatment of peripheral neuropathic pain. Making a minor structural change in C21 shifted the pharmacological profile, generating the regioisomer antagonist C38. The renewed interest in AT2R antagonists as potential drugs to treat neuropathic pain make continued studies of antagonist C38 highly interesting.  The aim of this thesis was to continue exploring the structure-activity relationship of antagonist C38 by investigating three chemical motifs to identify compounds with better drug-like properties. Developing a new chemical method, transesterification of sulfonyl carbamates, allowed quick modification of one of the motifs. Reducing the length of the sulfonyl carbamate chain significantly increased metabolic stability in liver microsomes without losing affinity for AT2R. Using a model substrate, the transesterification reaction was applied in a microwave heated continuous-flow system. Adding small substituents to the central phenyl ring generated a second library of ligands with retained affinity, but with no observed increase in metabolic stability. Docking studies with this library and a recently presented crystal structure of AT2R, resulted in a proposed binding mode of C38. Replacing the imidazole head group with bicyclic amides slightly improved affinity. While metabolic stability improved compared to previously published amide analogs, the bicyclic ligands were inferior to C38. Developing an assay based on RAW264.7 macrophages allowed a new evaluation of the functional activity exhibited by C38. In contrast to previous research, C21 and C38 both display agonistic functional activity in the macrophage assay. In summary, the work presented in this thesis expand the structure-activity relationship of C38 and its pharmacological profile. Two new ligands were identified that could serve as tools in murine models of neuropathic pain

Kan man det man lärt sig – om rymden?

Varför kan vi som vuxna inte mer om rymden? Varför verkar det ibland som om barn i årskurs tre vet mer? Dessa frågor ledde oss in på ämnet för vår uppsats. Är det så att skolans undervisning bygger på ytinlärning och att kunskap inte befästs på bästa sätt? Denna uppsats försöker visa hur undervisning skall ske för att förståelse skall uppnås och kunskap om rymden ska befästas och finnas kvar. Vår litteraturgenomgång visar hur viktigt det är att förstå hur inlärning sker. Vår egen undersökning visar att kunskap om rymden inte ökar med åldern, ska man generalisera kan man alltså påstå att vi inte får mer kunskap och erfarenhet kring rymden än vad vi har som 11-åringar

The IKEA experience : a case study on how different factors in the retail environment affect customer experience

IKEA is one of the world’s largest retailers in the world. They have managed to make their products and services more popular based not only on price but by creating a unique shopping experience for the customers. The purpose of this study is to provide a better understanding of the “IKEA experience.” In order to reach this purpose research questions focused on which factors affect the customer’s decision to visit IKEA and how the retail environment can be designed to enhance customer experience. Based on the research questions a literature review was conducted, resulting in a conceptual framework that was used to guide the data collection. The study has a qualitative case study approach where the primary data collection was through interviews with IKEA customers. The findings indicate that customers who choose to visit IKEA base their decision mainly on cost- advantages as well as the size of the assortment. The study found that social factors along with social activities also have an impact on the customers. The study also found that the customers plan their shopping at IKEA in advance because of the distance to the store, the size of the store, and the wide product assortment. Regarding the second research question, it was found that IKEA’s retail environment is used to enhance the customer experience. IKEA markets itself as a retailer that offers a large number of products in various designs for low prices. Our study indicates that IKEA is perceived by the customers in this way. IKEA’s customers also feel that there is uniqueness over IKEA and that they can not be compared to any other retailer. Customers are generally satisfied with their experiences at IKEA. Even though certain complications during their shopping experience might occur, customers would not hesitate to revisit the IKEA store.Validerat; 20101217 (root

Speech perception changes in the elderly : – a literature study

Andelen  äldre  i Sverige  ökar. Hos normalhörande  äldre människor  sker  det  en  förändring  i taluppfattningen som är en del av det naturliga åldrandet. Syftet med denna studie är att belysa det  biologiska  åldrandets  påverkan  på  den  åldrande  individens  taluppfattningsförmåga.  En systematisk  litteraturstudie  har  använts  som  metod.  Resultatet  från  övervägande  delen  av använda  artiklar  i  denna  studie  visar  att  normalhörande  äldre  har  sämre  taluppfattning  än normalhörande  yngre.  Den  försämrade  taluppfattningen  är  enligt  artiklarna  ett  resultat  av förändringar i det centrala hörselsystemet. Artiklarna pekar på att dessa förändringar beror på förändrad  lateralisering,  förlångsammad  kodning  av  talsignalen, minskad  nervaktivitet  eller förtvinade nerver i hörselkortex

Customer retention in service firms : three case studies of companies in the transport-logistic industry

Customer retention has increasingly become the focus of many companies' strategy. Through three case studies of Swedish companies in the transport- logistic industry this thesis investigates the extend companies within the service sector can enhance customer retention through customer relationship management. CRM is a business approach that focuses on ways companies build customer relationships with their customers. Companies may choose to apply different parts of CRM to their business: through technology and other means of communication with customers, various training programs and other resources devoted towards the employees of the company. Evaluating past and present customer behavior makes it possible for companies to adopt the most effective business strategy. Findings indicate that to be able to attract and keep customers, i.e., increase customer retention rate, companies have to adopt a proactive approach – devote time and resources to stay in touch with customers. In this way companies not only can increase their competitive advantage but install a sense of seeking benefits not just for the company but for their customers. A major conclusion of the study is that companies must recognize the impact of local culture and market conditions on companies’ business performance. Companies have to realize that they not only have to do the right things but have to do the things right: by listening to customers and adopting a strategy based on common grounds with customers a company stands better chance to outrank competitors and be more efficient in building strong relationships with their customers: hence increase customer retention.Validerat; 20101217 (root

Customer retention in service firms : three case studies of companies in the transport-logistic industry

Customer retention has increasingly become the focus of many companies' strategy. Through three case studies of Swedish companies in the transport- logistic industry this thesis investigates the extend companies within the service sector can enhance customer retention through customer relationship management. CRM is a business approach that focuses on ways companies build customer relationships with their customers. Companies may choose to apply different parts of CRM to their business: through technology and other means of communication with customers, various training programs and other resources devoted towards the employees of the company. Evaluating past and present customer behavior makes it possible for companies to adopt the most effective business strategy. Findings indicate that to be able to attract and keep customers, i.e., increase customer retention rate, companies have to adopt a proactive approach – devote time and resources to stay in touch with customers. In this way companies not only can increase their competitive advantage but install a sense of seeking benefits not just for the company but for their customers. A major conclusion of the study is that companies must recognize the impact of local culture and market conditions on companies’ business performance. Companies have to realize that they not only have to do the right things but have to do the things right: by listening to customers and adopting a strategy based on common grounds with customers a company stands better chance to outrank competitors and be more efficient in building strong relationships with their customers: hence increase customer retention.Validerat; 20101217 (root

The IKEA experience : a case study on how different factors in the retail environment affect customer experience

IKEA is one of the world’s largest retailers in the world. They have managed to make their products and services more popular based not only on price but by creating a unique shopping experience for the customers. The purpose of this study is to provide a better understanding of the “IKEA experience.” In order to reach this purpose research questions focused on which factors affect the customer’s decision to visit IKEA and how the retail environment can be designed to enhance customer experience. Based on the research questions a literature review was conducted, resulting in a conceptual framework that was used to guide the data collection. The study has a qualitative case study approach where the primary data collection was through interviews with IKEA customers. The findings indicate that customers who choose to visit IKEA base their decision mainly on cost- advantages as well as the size of the assortment. The study found that social factors along with social activities also have an impact on the customers. The study also found that the customers plan their shopping at IKEA in advance because of the distance to the store, the size of the store, and the wide product assortment. Regarding the second research question, it was found that IKEA’s retail environment is used to enhance the customer experience. IKEA markets itself as a retailer that offers a large number of products in various designs for low prices. Our study indicates that IKEA is perceived by the customers in this way. IKEA’s customers also feel that there is uniqueness over IKEA and that they can not be compared to any other retailer. Customers are generally satisfied with their experiences at IKEA. Even though certain complications during their shopping experience might occur, customers would not hesitate to revisit the IKEA store.Validerat; 20101217 (root